Crystal form and amorphous form of dezocine analogue hydrochloride

ABSTRACT

The present invention relates to a crystal form and an amorphous form of dezocine analogue hydrochloride, and in particularly, to a crystal form of a compound represented by formula (I) and an amorphous form of a compound represented by formula (II). An X-ray powder diffraction spectrum of the crystal form comprises characteristic peaks at 2θ values of 13.1°±0.2°, 16.8±0.2°, and 18.5±0.2°, and an X-ray powder diffraction spectrum of the amorphous form is shown in FIG. 1.

CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. national phase entry of PCT/CN2018/093721,filed on Jun. 29, 2018, which claims the priority of Chinese patentapplication CN201710532702.8 filed on Jul. 3, 2017, the contents ofwhich are hereby incorporated into the application.

TECHNICAL FIELD

The present invention relates to a crystal form and an amorphous form ofdezocine analogue hydrochloride, and more particularly, to a crystalform of a compound represented by formula (I) and an amorphous form of acompound represented by formula (II).

BACKGROUND

Dezocine, with a chemical name of(−)-[5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-3-ol, belongs to a typical opioid alkaloid analgesicdeveloped by Swedish Astra Company. This kind of drugs plays a role byexciting an opioid receptor. Dezocine has a stronger analgesic effectthan pentazocine, is a κ receptor agonist, and is also a μ receptorantagonist. Dezocine is less addictive and is suitable for treatingmoderate to severe pain after surgery, visceral colic and pain ofpatients with advanced cancer. Due to excellent tolerance and safety,dezocine is expected to become an opioid alkaloid analgesic with a goodmarket prospect.

Dezocine has a structure as follows:

Different solid forms of pharmaceutical active ingredients may havedifferent properties. Property changes of different solid forms canprovide improved formulations, for example, ease of synthesis orhandling, and improvement of stability and guarantee period. Propertychanges caused by different solid forms can also improve a final dosageform. Different solid forms of active pharmaceutical ingredients canalso generate polycrystalline form or other crystal forms, thusproviding more opportunities to evaluate the property changes of onesolid active pharmaceutical ingredient.

TECHNICAL EFFECT

The crystal form of the compound represented by formula (I) and theamorphous form of the compound represented by formula (II) according tothe present invention have simple preparation processes, and arerelatively stable, less influenced by light and heat humidity, andconvenient for preparation.

SUMMARY

In one aspect, the present invention provides a crystal form of acompound represented by formula (I),

wherein an X-ray powder diffraction spectrum of the crystal formcomprises characteristic peaks at 2θ values of 13.07°±0.2°, 16.84±0.2°,and 18.51±0.2°.

In some solutions of the present invention, the X-ray powder diffractionspectrum of the crystal form of the compound represented by formula (I)comprises characteristic peaks at 2θ values of 13.07°±0.2°, 15.30°±0.2°,16.84°±0.2°, 18.51°±0.2°, 21.44°±0.2°, 23.18°±0.2°, 24.04°±0.2° and26.20°±0.2.

In some solutions of the present invention, the X-ray powder diffractionspectrum of the crystal form of the compound represented by formula (I)is shown in FIG. 4.

In some solutions of the present invention, the X-ray powder diffractionspectrum of the crystal form of the compound represented by formula (I)is shown in FIG. 1.

TABLE 1 XRPD Diffraction Data of Crystal form of Compound Represented byFormula (I) 2θ angle Interplanar Relative No. (°) distance (Å) intensity(%) 1 12.415 7.1239 28.9 2 13.065 6.7708 100 3 14.05 6.2981 6.5 4 14.7236.0118 21.7 5 15.061 5.8777 19.8 6 15.297 5.7875 28.5 7 16.073 5.509910.7 8 16.838 5.2611 38.7 9 17.364 5.1027 7.4 10 18.513 4.7886 57.2 1119.581 4.5299 7.2 12 20.273 4.3766 24.6 13 20.686 4.2903 8.9 14 21.4374.1416 29.7 15 22.033 4.031 21.5 16 23.016 3.8609 29.7 17 23.177 3.834543.1 18 24.044 3.6981 38.7 19 25.032 3.5544 10.8 20 25.395 3.5044 8.9 2126.197 3.3989 45 22 27.914 3.1936 22.2 23 28.171 3.1651 14.5 24 30.5462.9242 10.6

In some solutions of the present invention, a DSC curve of the crystalform of the compound represented by formula (I) comprises twoendothermic peaks at 73.71° C.±3° C. and 245.82° C.±3° C.

In some solutions of the present invention, the DSC curve of the crystalform of the compound represented by formula (I) is shown in FIG. 5.

In some solutions of the present invention, when a TGA curve of thecrystal form of the compound represented by formula (I) is at 120.00°C.±3° C., a weight is reduced by 5.812%; and when the TGA curve of thecrystal form of the compound represented by formula (I) is at 200.12°C.±3° C., the weight is reduced by 6.5748%.

In some solutions of the present invention, the TGA curve of the crystalform of the compound represented by formula (I) is shown in FIG. 6.

In another aspect, the present invention provides an amorphous form of acompound represented by formula (II),

wherein an X-ray powder diffraction spectrum of the amorphous form isshown in FIG. 1.

In some solutions of the present invention, a MDSC curve of theamorphous form of the compound represented by formula (II) undergoesglass transition at 79.07° C.±3° C.

In some solutions of the present invention, the MDSC curve of theamorphous form of the compound represented by formula (II) is shown inFIG. 2.

In some solutions of the present invention, when a TGA curve of thecompound represented by formula (II) is at 120.00° C., a weight isreduced by 4.270%; and when the TGA curve of the compound represented byformula (II) is at 199.60° C.±3° C., the weight is reduced by 5.1553%.

In some solutions of the present invention, the TGA curve of thecompound represented by formula (II) is shown in FIG. 3.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein areintended to have the following meanings. A specific term or phrase shallnot be considered as being uncertain or unclear in case of no specificdefinitions, and shall be understood according to the ordinary meanings.Any commodity name herein is intended to refer to the correspondingcommodity thereof or the active ingredients thereof.

The intermediate compounds of the present invention may be prepared by avariety of synthesis methods known by those skilled in the art,including the specific embodiments listed below, the embodiments formedby combination with other chemical synthesis methods, and equivalentreplacements known by those skilled in the art. The preferredembodiments include but are not limited to the embodiments of thepresent invention.

The chemical reactions of the specific embodiments of the presentinvention are completed in suitable solvents, and the solvents must besuitable for the chemical changes of the present invention and therequired reagents and materials. In order to obtain the compounds of thepresent invention, those skilled in the art sometimes need to modify orselect the synthesis steps or reaction flows based on the existingembodiments.

The present invention will be described in detail below with referenceto the embodiments, and the embodiments are not meant to limit thepresent invention in any way.

All the solvents used in the present invention are commerciallyavailable and may be used without further purification.

The solvents used in the present invention are commercially available.

The following abbreviations are used in the present invention:

DMF: N,N-dimethylformamide; Boc₂O: Boc anhydride; EDCI:1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; and DMAP:4-dimethylaminopyridine.

Instrument and Analysis Method

1.1 X-Ray Powder Diffractometer (XRPD)

-   -   Instrument model: Bruker D8 advance X-ray diffractometer    -   Test method: about 10 mg to 20 mg of sample is used for XRPD        detection.    -   Specific XRPD parameters are as follows:    -   light tube: Cu, kα (λ=1.54056 Å)    -   light tube voltage: 40 kV, light tube current: 40 mA    -   divergence slit: 0.60 mm    -   detector slit: 10.50 mm    -   anti-scattering slit: 7.10 mm    -   scanning scope: 4 deg to 40 deg    -   step size: 0.02 deg    -   step length: 0.12 s    -   rotating speed of sample disk: 15 rpm

1.2 Differential Scanning calorimeter (DSC)

-   -   Instrument model: TA Q2000 differential scanning calorimeter    -   Test method: a sample (˜1 mg) is placed in a DSC aluminum pot        for testing, and under the condition of 50 mL/min N₂, the sample        is heated from a room temperature to 300° C. at a heating rate        of 10° C./min.

1.3 Modulated Differential Scanning calorimeter (MDSC)

-   -   Instrument model: TA Q2000 differential scanning calorimeter    -   Test method: a sample (˜2 mg) is placed in a DSC aluminum pot        for testing, and under the condition of 50 mL/min N₂, the sample        is heated from 0° C. to 200° C. at a heating rate of 2° C./min,        an amplitude of 1° C. and a period of 60 s.

1.4 Thermal Gravimetric Analyzer (TGA)

-   -   Instrument model: TA Q5000 thermal gravimetric analyzer    -   Test method: a sample (2 mg to 5 mg) is placed in a TGA platinum        pot for testing, and under the condition of 25 mL/min N₂, the        sample is heated from a room temperature to 20% weight loss at a        heating rate of 10° C./min.

1.5 High Performance Liquid Chromatograph (HPLC)

-   -   Instrument model: Agilent 1200 high performance liquid        chromatograph    -   The analysis method is as follows:

TABLE A Determination Method for Content by HPLC Analysis Device Agilent1200 high performance liquid chromatograph ChromatographicWaters-Xbridge C18 (150 mm × 4.6 mm, 3.5 μm) column Mobile phase A 0.1%trifluoroacetic acid solution Mobile phase B 0.1% trifluoroacetic acidacetonitrile solution Flow rate 1.0 mL/min Injection volume 10.0 μLDetection 215 nm wavelength Column 35° C. temperature DiluentAcetonitrile: pure water 2/1 (v/v) Gradient elution Time Mobile Mobileprocedure (min) phase A (%) phase B (%) 0.01 50 50 5.00 20 80 7.00 20 807.01 50 50 15.00 50 50

TABLE B Determination Method for Related Substance by HPLC AnalysisDevice Agilent 1200 high performance liquid chromatographChromatographic Waters-Xbridge C18 (150 mm × 4.6 mm, 3.5 μm) columnMobile phase A 0.1% trifluoroacetic acid solution Mobile phase B 0.1%trifluoroacetic acid acetonitrile solution Flow rate 1.0 mL/minInjection volume 10.0 μL Detection 215 nm wavelength Column 35° C.temperature Diluent Acetonitrile: pure water 2/1 (v/v) Gradient elutionTime Mobile Mobile procedure (min) phase A (%) phase B (%) 0.00 80 2010.00 55 45 40.00 0 100 50.00 0 100 50.01 80 20 60.00 80 20

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an XRPD spectrum of an amorphous form of a compoundrepresented by formula (II).

FIG. 2 is a MDSC spectrum of the amorphous form of the compoundrepresented by formula (II).

FIG. 3 is a TGA spectrum of the amorphous form of the compoundrepresented by formula (II).

FIG. 4 is an XRPD spectrum of a crystal form of a compound representedby formula (I).

FIG. 5 is a DSC spectrum of the crystal form of the compound representedby formula (I).

FIG. 6 is a TGA spectrum of the crystal form of the compound representedby formula (I).

DETAILED DESCRIPTION

The present invention will be described in detail hereinafter withreference to the embodiments, but it is not meant to be anydisadvantageous limitation to the present invention. The presentinvention has been described in detail herein, and specific embodimentsthereof have also been disclosed. It will be apparent to those skilledin the art that various changes and modifications can be made to thespecific embodiments of the present invention without departing from thespirit and scope of the present invention.

Preparation of Embodiments Preparation of Intermediate I-3

A compound I-1 (100.0 g, 339.69 mmol) and a compound I-2 (133.8 g,509.54 mmol) were dissolved in anhydrous toluene (1.0 L), and thereaction solution was heated to 120° C. and continuously stirred for 16h. After thermal filtration, the filtered solid was re-dispersed in 500mL of toluene, the mixture was heated to reflux, thermally filtered, anddried in vacuum to obtain a compound I-3, and the compound was directlyused in next reaction without further purification.

¹H NMR (400 MHz, CD₃OD): δ 8.98 to 8.97 (d, J=4.4 Hz, 1H), 8.46 (s, 2H),8.32 to 8.27 (m, 2H), 8.19 to 8.15 (m, 1H), 7.99 to 7.98 (m, 1H), 7.88to 7.82 (m, 2H), 6.67 (s, 1H), 5.75 to 5.66 (m, 1H), 5.47 to 5.42 (m,1H), 5.20 to 5.16 (m, 2H), 5.05 to 5.02 (m, 1H), 4.62 to 4.60 (m, 1H),4.08 to 4.05 (m, 1H), 3.75 to 3.65 (m, 1H), 3.52 to 3.46 (m, 1H), 3.43to 3.40 (m, 1H), 2.76 (brs, 1H), 2.34 to 2.26 (m, 2H), 2.12 (brs, 1H),1.95 to 1.90 (m, 1H), 1.49 to 1.44 (m, 1H); LCMS (ESI) m/z:521.1 [M+1]⁺.

Embodiment 1: Synthesis of Compound 1

Step 1: Preparation of Compound 1-2

A compound 1-1 (5.0 kg, 24.58 mol) was added into anhydrousdichloromethane (31.0 L), then succinic anhydride (2.7 kg, 27.18 mol)and aluminum trichloride (6.7 kg, 50.32 mol) were added at once, and thereaction solution was continuously stirred at 20° C. to 25° C. for 20 h.The reaction solution was slowly poured into 60 L of ice water to stirand quench, then 1 L of concentrated hydrochloric acid was added tocontinuously stir the mixture for 5 min, and a large amount of whitesolids were generated. The mixture was filtered, and a filter cake waswashed with 5 L of water and dried in vacuum to obtain a compound 1-2.

¹H NMR (400 MHz, CDCl₃): δ 8.19 to 8.16 (m, 1H), 6.69 to 6.66 (d, J=12.4Hz, 1H), 3.98 (s, 3H), 3.30 to 3.26 (m, 2H), 2.82 to 2.79 (m, 2H). LCMS(ESI) m/z: 304.9 [M+1]⁺.

Step 2: Preparation of Compound 1-3

The compound 1-2 (7.5 kg, 24.61 mol) was added into trifluoroacetic acid(8.9 kg, 78.52 mol, 5.81 L) at 20° C., triethyl silane (8.8 kg, 76.06mol) was slowly added in batches, and a reaction solution was heated to95° C. and continuously stirred for 16 h. The reaction solution wascooled to a room temperature, 10 L of petroleum ether was added, and alarge amount of pink solids were precipitated. The mixture was filtered,and a filter cake was washed with 10 L of petroleum ether and dried invacuum to obtain a compound 1-3.

¹H NMR (400 MHz, CD₃OD): δ 7.43 to 7.41 (d, J=8.0 Hz, 1H), 6.86 to 6.83(d, J=11.6 Hz, 1H), 3.87 (s, 3H), 2.65 to 2.61 (t, J=7.6 Hz, 2H), 2.34to 2.30 (t, J=7.6 Hz, 2H), 1.91 to 1.83 (m, 2H). LCMS (ESI) m/z: 290.8[M+1]⁺.

Step 3: Preparation of Compound 1-4

The compound 1-3 (1.1 kg, 3.92 mol) was dissolved in methanol (4.5 L)under an argon atmosphere, then wet palladium carbon (80.0 g, 10%) wasadded into a solution obtained, hydrogen replacement was conducted threetimes, and then the reaction solution was continuously stirred in a highpressure kettle at 50° C. for 48 h under 2.5 Mpa. The reaction solutionwas cooled down, and then taken out slowly; 500 mL of concentratedhydrochloric acid was added to stir until homogeneous, then the mixturewas filtered, and a filter cake was washed with 2 L of methanol. Thecombined filter solution was adjusted with 50% sodium hydroxide solutionto a pH was 10 to 11. An organic solvent was removed under reducedpressure, then the mixture was extracted twice with 4 L of ethylacetate, and a combined organic phase was dried with anhydrous sodiumsulfate and concentrated to obtain a crude compound 1-4, and thecompound was directly used in next reaction without furtherpurification.

¹H NMR (400 MHz, CD₃OD): δ 7.10 to 7.05 (m, 1H), 6.65 to 6.28 (m, 2H),3.80 (s, 3H), 2.67 to 2.63 (t, J=7.2 Hz, 2H), 2.40 to 2.36 (t, J=7.6 Hz,2H), 1.97 to 1.89 (m, 2H).

Step 4: Preparation of Compound 1-5

The compound 1-4 (596.0 g, 2.81 mol) was dissolved in anhydrousdichloromethane (2.0 L) at 15° C., 2 mL of anhydrous DMF was added,oxalyl chloride (427.8 g, 3.37 mol, 295.01 mL) was slowly addeddropwise, and the reaction solution was continuously stirred at thetemperature for 0.5 h. An organic solvent of the reaction solution wasremoved under reduced pressure, 200 mL of anhydrous dichloromethane wasadded into a crude product, an organic solvent was removed under reducedpressure, and a crude product compound 1-5 was directly used for nextreaction without purification.

Step 5: Preparation of Compound 1-6

The crude product 1-5 (202.0 g, 875.75 mmol) was dissolved in anhydrousdichloromethane (4.0 L) at 25° C., powdery anhydrous aluminumtrichloride (105.1 g, 788.17 mmol) was added at once, and the reactionsolution was continuously stirred at 20° C. for 7 min. The reactionsolution was poured into 1 L of ice water stirred, then the solution wasseparated, a water phase was extracted once with 1 L of dichloromethane,an organic phase was combined, an organic solvent was removed underreduced pressure, and an obtained crude product was separated andpurified by silica gel column chromatography (petroleum ether:ethylacetate=10:1 (v:v)) to obtain a compound 1-6.

¹H NMR (400 MHz, CDCl₃): δ 7.37 to 7.36 (d, J=2.4 Hz, 1H), 6.85 to 6.82(m, 1H), 3.84 (s, 3H), 2.90 to 2.87 (t, J=6.4 Hz, 2H), 2.68 to 2.65 (t,J=6.4 Hz, 2H), 2.17 to 2.11 (m, 2H).

Step 6: Preparation of Compound 1-7

The compound 1-6 (1.0 kg, 5.15 mol) was dissolved in anhydrous toluene(4.0 L) under the protection of nitrogen, methylmagnesium bromide (3 M,2.1 L, 5.15 mol) was added dropwise under the condition of ice-waterbath, an internal temperature was kept not to exceed 10° C. during thedropwise adding process, and then the reaction solution was slowlyheated to 25° C. and continuously stirred for 16 h. The reactionsolution was poured into 4 L of saturated ammonium chloride solution, aliquid was separated, a water phase was extracted twice with 5 L ofethyl acetate, a combined organic phase was washed once with 3 L ofsaturated saline solution, an organic solvent was removed under reducedpressure to obtain a compound 1-7, and the compound was directly used innext reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 6.98 to 6.97 (d, J=1.6 Hz, 1H), 6.56 to 6.53(m, 1H), 3.87 (s, 3H), 2.70 to 2.67 (m, 2H), 1.99 to 1.80 (m, 4H), 1.56(s, 3H).

Step 7: Preparation of Compound 1-8

The crude product 1-7 (1.8 kg, 8.75 mol) was dissolved in acetonitrile(1.0 L) at 25° C., 6 N hydrochloric acid (2.5 L) was added, and thereaction solution was continuously stirred for 16 h. 4 L of ethylacetate was added, a liquid was separated, a water phase was extractedfor three times with 5 L of ethyl acetate, a combined organic phase waswashed with 3 L of saturated saline solution, an organic solvent wasremoved under reduced pressure to obtain a crude product 1-8, and thecompound was directly used in next reaction without furtherpurification.

¹H NMR (400 MHz, CDCl₃): δ 6.63 to 6.62 (d, J=2.0 Hz, 1H), 6.51 to 6.48(m, 1H), 5.93 to 5.90 (m, 1H), 3.80 (s, 3H), 2.73 to 2.69 (t, J=8.0 Hz,2H), 2.25 to 2.22 (m, 2H), 2.04 to 2.03 (d, J=3.2 Hz, 3H).

Step 8: Preparation of Compound 1-9

The compound 1-8 (493.0 g, 2.56 mol) was dissolved in a mixed solvent ofacetone (2.0 L) and water (2.0 L) at 25° C., sodium bicarbonate (861.8g, 10.26 mol) was added, then potassium peroxymonosulfate (1.0 kg, 1.67mol) was slowly added in batches, an internal temperature was controllednot to exceed 30° C. during the adding process, and the reactionsolution was continuously stirred at the temperature for 1.5 h. 2 L ofsaturated sodium sulfite solution was slowly added into the reactionsolution, a test by starch potassium iodide paper showed no color changeto blue, the mixture was placed still, a supernatant was taken out, thesolid was washed with 1.5 L of dichloromethane for three times, thesupernatant and the dichloromethane cleaning solution were combined, aliquid was separated, a water phase was extracted with 6 L ofdichloromethane, a combined organic phase was washed with 6 L ofsaturated saline solution and dried with anhydrous sodium sulfate, thesolution was filtered and concentrated under reduced pressure, tests bystarch potassium iodide paper showed no color change to blue in theconcentration process, a crude product 1-9 was obtained, and thecompound was directly used in next reaction without furtherpurification.

Step 9: Preparation of Compound 1-10

The crude compound 1-9 (450.0 g, 2.16 mol) was dissolved in anhydrousdichloromethane (3.0 L) at 0° C., an anhydrous dichloromethane (100 mL)solution of a boron trifluoride etherate complex (30.7 g, 216.00 mmol,26.67 mL) was slowly added dropwise into an obtained solution, and areaction solution was continuously stirred for 30 min. The reactionsolution was slowly poured into 1.5 L of saturated sodium carbonatesolution, an organic phase was separated, a water phase was extractedtwice with 1.5 L of dichloromethane, a combined organic phase was washedwith 2 L of saturated saline solution and dried with anhydrous sodiumsulfate, the solution was filtered, an organic solvent was removed underreduced pressure, and an obtained crude product was separated andpurified by silica gel column chromatography (petroleum ether:ethylacetate=15:1 (v:v)) to obtain a compound 1-10.

¹H NMR (400 MHz, CDCl₃): δ 6.59 to 6.52 (m, 2H), 3.79 (s, 3H), 3.49 to3.47 (m, 1H), 3.14 to 3.10 (m, 1H), 2.99 to 2.85 (m, 1H), 2.58 to 2.48(m, 2H), 1.46 to 1.44 (d, J=7.6 Hz, 3H).

Step 10: Preparation of Compound 1-11

The compound 1-10 (448.0 g, 2.15 mol) and 1,5-dibromopentane (1.5 kg,6.45 mol) were dissolved in a mixed solvent of toluene (30.0 L) anddichloromethane (3.0 L), then the compound 1-3 (119.8 g, 215.00 mmol)was added, 50% potassium hydroxide solution (3.0 L) was slowly anddropwise added under a nitrogen atmosphere, and a reaction solution washeated to 15° C. and continuously stirred for 20 h. 6 L of saturatedsaline solution was added, a liquid was separated, a water phase wasextracted with 6 L of ethyl acetate, an organic solvent was removed froma combined organic phase under reduced pressure, and an obtained crudeproduct was separated and purified by silica gel column chromatography(petroleum ether: ethyl acetate=20:1 (v:v)) to obtain a compound 1-11.

¹H NMR (400 MHz, CDCl₃): δ 6.63 to 6.62 (d, J=2.0 Hz, 1H), 6.56 to 6.53(m, 1H), 3.81 (s, 3H), 3.34 to 3.30 (t, J=7.2 Hz, 2H), 3.14 to 3.10 (m,1H), 2.95 to 2.85 (m, 1H), 2.65 to 2.57 (m, 2H), 2.23 to 2.08 (m, 1H),1.77 to 1.73 (m, 2H), 1.70 to 1.58 (m, 1H), 1.39 (s, 3H), 1.34 to 1.30(m, 2H), 0.97 to 0.94 (m, 2H).

An ee value of the compound was 58.7%, where the RRT were 1.782 and1.954 respectively.

Step 11: Preparation of Compound 1-12

The compound 1-11 (1.1 kg, 3.05 mol) was dissolved in dimethyl sulfoxide(7.0 L) at 0° C., sodium tert-butoxide (351.8 g, 3.66 mol) was slowlyadded in batches, an internal temperature was kept not to exceed 30° C.,and a reaction solution was continuously stirred for 30 min. Thereaction solution was slowly poured into 6 L of ice water, 6 L of ethylacetate was added, a liquid was separated, a water phase was extractedwith 20 L of ethyl acetate, a combined organic phase was washed with 20L of saturated saline solution, an organic solvent was removed underreduced pressure, and a crude product was separated and purified bysilica gel column chromatography (petroleum ether:ethyl acetate=20:1(v:v)) to obtain a compound 1-12.

¹H NMR (400 MHz, CDCl₃): δ 6.54 to 6.53 (d, J=2.0 Hz, 1H), 6.47 to 6.43(m, 1H), 3.72 (s, 3H), 3.02 to 2.98 (m, 1H), 2.86 to 2.80 (m, 1H), 2.70to 2.68 (m, 1H), 2.35 to 2.25 (m, 1H), 1.81 to 1.78 (m, 1H), 1.71 to1.68 (m, 2H), 1.52 to 1.47 (m, 4H), 1.27 (s, 3H), 1.26 to 1.23 (m, 2H).

Step 12: Preparation of Compound 1-13

The compound 1-12 (882.0 g, 3.19 mol) was dissolved in ethanol (3.0 L),then pyridine (2.5 kg, 31.92 mol, 2.58 L) and hydroxylaminehydrochloride (2.2 kg, 31.92 mol) were added into an obtained solution,and the reaction solution was heated to 100° C. and continuously stirredfor 24 h. The reaction solution was poured into 6 L of ethyl acetate, 4L of water was added, a liquid was separated, a water phase wasextracted twice with 4 L of ethyl acetate, a combined organic phase waswashed with 4 L of hydrochloric acid (4N), washed with 4 L of saturatedsaline solution and dried with anhydrous sodium sulfate, an organicsolvent was removed under reduced pressure to obtain a crude product1-13, and the compound was directly used in next reaction withoutfurther purification.

1H NMR (400 MHz, CDCl₃): δ 6.57 to 6.56 (d, J=1.6 Hz, 1H), 6.44 to 6.39(m, 1H), 3.74 to 3.66 (m, 4H), 2.88 to 2.84 (m, 1H), 2.78 to 2.76 (m,1H), 2.21 to 2.20 (m, 1H), 2.08 to 2.03 (m, 1H), 1.56 to 1.48 (m, 6H),1.46 (s, 3H), 1.45 to 1.40 (m, 2H).

Step 13: Preparation of Compound 1-14

The compound 1-13 (404.0 g, 1.39 mol) was dissolved in methanol (7.0 L),ammonia water (130.3 g, 929.02 mmol, 143.13 mL) was added, Raney nickel(377.8 g, 2.20 mol) was added under an argon atmosphere, hydrogenreplacement was conducted three times, and the reaction solution wascontinuously stirred in a high pressure kettle with 3 Mpa hydrogen at80° C. to 85° C. for 72 h. The reaction solution was cooled to a roomtemperature and filtered under an argon atmosphere, a filter cake waswashed with 1 L of methanol, an organic solvent was removed underreduced pressure to obtain a crude product 1-14, and the compound wasdirectly used in next reaction without further purification.

¹H NMR (400 MHz, CDCl₃): δ 6.57 to 6.56 (d, J=1.6 Hz, 1H), 6.44 to 6.39(m, 1H), 3.74 to 3.66 (m, 4H), 2.88 to 2.84 (m, 1H), 2.78 to 2.76 (m,1H), 2.21 to 2.20 (m, 1H), 2.08 to 2.03 (m, 1H), 1.56 to 1.48 (m, 6H),1.46 (s, 3H), 1.45 to 1.40 (m, 2H).

Step 14: Preparation of Compound 1-15

The compound 1-14 (756.0 g, 2.73 mol) was dissolved in a mixed solutionof ethyl acetate (750 mL) and methanol (2.3 L), then D-tartaric acid(250.0 g, 1.67 mol) was added into the mixed solution, the reactionsolution was heated to 80° C. to 85° C. and continuously stirred for 1h, white solid was generated, water (750 mL) was added, and the reactionsolution was continuously stirred at 80° C. to 85° C. for 2 h, slowlycooled to a room temperature and placed still for 24 h. The reactionsolution was filtered, and a filter cake was washed with 1 L of ethylacetate and dried in vacuum to obtain tartrate of the compound 1-15.

¹H NMR (400 MHz, CD₃OD): δ 6.67 to 6.66 (m, 1H), 6.63 to 6.60 (m, 1H),4.40 (s, 2H), 3.78 (s, 3H), 3.68 to 3.65 (m, 1H), 2.93 to 2.90 (m, 2H),2.56 to 2.54 (m, 1H), 1.97 to 1.85 (m, 2H), 1.78 to 1.70 (m, 2H), 1.61to 1.57 (m, 3H), 1.49 (s, 3H), 1.21 to 1.18 (m, 1H), 0.90 to 0.84 (m,2H). LCMS (ESI) m/z: 278.1 [M+1]⁺.

An ee value of the compound was 99.1%, where the RRT were 2.726 and3.205 respectively.

Step 15: Preparation of Compound 1-16

The compound 1-15 (162.0 g, 378.98 mmol) was added into 40% hydrobromicacid solution (710 mL), and the reaction solution was heated to 120° C.and continuously stirred for 72 h. The reaction solution was cooled andfiltered, and a filter cake was washed with 1.5 L of water and dried invacuum to obtain hydrobromide of the compound 1-16.

¹H NMR (400 MHz, CD₃OD): δ 6.67 to 6.66 (d, J=0.8 Hz, 1H), 6.47 to 6.4 3(m, 1H), 3.69 to 3.67 (m, 1H), 2.93 to 2.90 (m, 2H), 2.57 to 2.55 (m,1H), 1.98 to 1.92 (m, 2H), 1.79 to 1.59 (m, 5H), 1.48 (s, 3H), 1.24 to1.21 (m, 1H), 0.92 to 0.89 (m, 2H). LCMS (ESI) m/z: 264.0 [M+1]⁺.

An ee value of the compound was 99.5%, where the RRT were 3.228 and3.966 respectively.

Step 16: Preparation of Compound 1-17

The compound 1-16 (170.1 g, 494.05 mmol) was dissolved in anhydroustetrahydrofuran (1200 mL), triethylamine (104.0 mL, 750.3 mmol) wasadded, (Boc)₂O (108.2 g, 495.81 mmol) was slowly added dropwise, and thereaction solution was continuously stirred at 30° C. for 16 h. Thereaction solution was poured into 2 L of water and extracted with 800 mLof ethyl acetate, a liquid was separated, and a water phase wasextracted twice with 800 mL of ethyl acetate. A combined organic phasewas washed with 1 L of saturated saline solution and dried withanhydrous sodium sulfate, and an organic solvent was removed underreduced pressure. A crude product was heated and dispersed in 1200 mL ofmixed solvent of n-heptane and ethyl acetate (5:1 (v:v)), the mixturewas placed still overnight and filtered, and a filter cake was dried invacuum to obtain a compound 1-17.

¹H NMR (400 MHz, CD₃OD): δ 6.52 to 6.51 (d, J=1.2 Hz, 1H), 6.39 to 6.34(m, 1H), 4.04 to 4.00 (m, 1H), 2.89 to 2.76 (m, 2H), 2.30 to 2.29 (m,1H), 1.83 to 1.71 (m, 4H), 1.58 to 1.51 (m, 12H), 1.28 to 1.26 (m, 4H),0.96 to 0.90 (m, 2H). LCMS (ESI) m/z: 308.0 [M to 56+1]⁺.

Step 17: Preparation of Compound 1-18

The compound 1-17 (155.1 g, 426.72 mmol) was added into anhydrousdichloromethane (2.0 L), DMAP (26.1 g, 213.36 mmol), decanedioic acid(43.2 g, 213.36 mmol) and EDCI (106.3 g, 554.73 mmol) were added insequence, and the reaction solution was continuously stirred at 30° C.for 16 h. The reaction solution was poured into 2 L of water, a liquidwas separated, and a water phase was extracted twice with 850 mL ofdichloromethane. A combined organic phase was washed with 1.5 L ofsaturated saline solution and dried with anhydrous sodium sulfate, anorganic solvent was removed under reduced pressure, and a crude productwas separated and purified by silica gel column chromatography(petroleum ether:ethyl acetate=10:1-3:1 (v:v)) to obtain a compound1-18.

¹H NMR (400 MHz, CDCl₃): δ 6.76 (s, 2H), 6.71 to 6.69 (m, 2H), 4.96 to4.93 (d, J=10.4 Hz, 2H), 4.13 to 4.09 (m, 2H), 2.96 to 2.85 (m, 4H),2.58 to 2.54 (t, J=7.6 Hz, 1H), 2.42 (brs, 2H), 1.79 to 1.51 (m, 31H),1.49 to 1.28 (m, 21H), 0.96 to 0.90 (m, 4H). LCMS (ESI) m/z: 893.6[M+1]⁺.

Step 18: Preparation of Compound 1

The compound 1-18 (120.0 g, 134.39 mmol) was dissolved in ethyl acetate(410 mL), an ethyl acetate solution of 4 M hydrogen chloride (500 mL)was added at once, and the reaction solution was continuously stirred ata room temperature for 2 h until no gas was generated. The reactionsolution was filtered under a nitrogen atmosphere, and a filter cake waswashed with 300 mL of ethyl acetate and dried in vacuum to obtainhydrochloride of the compound 1.

¹H NMR (400 MHz, CD₃OD): δ 6.83 (s, 2H), 6.73 to 6.71 (m, 2H), 4.03 to4.00 (m, 2H), 2.93 to 2.89 (m, 4H), 2.52 to 2.49 (m, 6H), 1.90 to 1.86(m, 4H), 1.69 to 1.63 (m, 8H), 1.52 to 1.49 (m, 6H), 1.41 (s, 6H), 1.40to 1.33 (m, 8H), 1.18 to 1.12 (m, 2H), 0.79 to 0.72 (m, 4H). LCMS (ESI)m/z: 693.5 [M+1]⁺.

Chiral analysis methods for the compound 1-11 and the compound 1-15 areshown in Table C below:

TABLE C Chiral Analysis Methods for Compound 1-11 and Compound 1-15Device Supercritical liquid chromatograph equipped with ultravioletdetector Chromatographic Chiralpak AY-3 150 × 4.6 mm I.D., 3 μm columnMobile phase A Supercritical carbon dioxide Mobile phase B Ethanol(containing 0.05% diethylamine) Flow rate 2.5 mL/min Detectionwavelength 220 nm Column temperature 35° C. Diluent Methanol Gradientelution Time Mobile Mobile procedure (min) phase A (%) phase B (%) 0.0095 5 5.00 60 40 7.50 60 40 7.51 95 5 10.00 95 5

A chiral analysis method for the compound 1-16 is shown in Table Dbelow:

TABLE D Chiral Analysis Method for Compound 1-16 Device Supercriticalliquid chromatograph equipped with ultraviolet detector Chromatographiccolumn Chiralpak AD-3 100 × 4.6 mm I.D., 3 μm Mobile phase ASupercritical carbon dioxide Mobile phase B Ethanol (containing 0.05%diethylamine) Flow rate 2.8 mL/min Detection wavelength 280 nm Columntemperature 40° C. Diluent Methanol Gradient elution Time Mobile Mobileprocedure (min) phase A (%) phase B (%) 0.00 95 5 4.50 60 40 7.00 60 407.01 95 5 8.00 95 5

Embodiment 2: Preparation of Amorphous Form Sample of CompoundRepresented by Formula (II)

An appropriate amount of raw material compound 1 was added into an agatemortar and grinded for 60 min to obtain the sample.

An XRPD detection result is shown in FIG. 1, and MDSC and TGA detectionresults are shown in FIGS. 2 and 3.

Embodiment 3: Preparation of Crystal Form Sample of Compound Representedby Formula (I)

200 mg of raw material compound 1 was added into 2.0 mL ofacetonitrile-water mixed solvent (90:10, v:v). The mixture wasmagnetically stirred at 37° C. for 2 days, and after centrifugation, aresidual solid sample was placed in a vacuum drying oven (35° C.) anddried for 3 days. An XRPD detection result is shown in FIG. 4 and Table1, and DSC and TGA detection results are shown in FIGS. 5 and 6.

Characterization of Embodiments Embodiment 1: Solid Stability Test

1. Solid Stability Test of Crystal Form of Compound Represented byFormula (I)

According to the Guiding Principles for Stability Experiment of CrudeDrugs and Preparations (General Rules 9001 of Chinese Pharmacopoeia(2015 Version) Volume IV), a stability of a compound placed underconditions of high temperature (60° C., open), high humidity (RT/92.5%RH, open) and illumination (50001×, closed) for 5 days and 10 days wereinvestigated.

An appropriate amount of a crystal form sample of a compound representedby formula (I) was placed at a bottom of a glass sample bottle andspread into a thin layer. The sample placed under the conditions of hightemperature and high humidity was sealed with aluminum-foil paper, andsmall holes were punched in the aluminum-foil paper to ensure that thesample could be fully contacted with ambient air. The sample placedunder the condition of illumination (50001×) was sealed with a bottlecap and further sealed with a sealing film, the sample was sealed andplaced at a room temperature, and XRPD detection was performed on the5^(th) day and the 10^(th) day. The detection results were compared withan initial detection result of 0 day, all crystal forms of resultsamples did not change, and the test results are shown in Table 2 below.

TABLE 2 Solid Stability Test of Crystal Form of Compound Represented byFormula (I) Time Test condition point Crystal form (MOD) —  0 dayCrystal form of compound represented by formula (I) High temperature  5days Crystal form of compound represented (60° C., open) by formula (I)10 days Crystal form of compound represented by formula (I) Highhumidity (RT/  5 days Crystal form of compound represented RH 92.5%,open) by formula (I) 10 days Crystal form of compound represented byformula (I) Illumination  5 days Crystal form of compound represented(5000lx, closed) by formula (I) 10 days Crystal form of compoundrepresented by formula (I)

The result showed that the crystal form of the compound was stable underthe conditions of high temperature, high humidity and illuminationwithout any change.

2. Solid Stability Test of Amorphous Form of Compound Represented byFormula (II)

Stability of amorphous form sample under conditions of high temperature,high humidity (40° C./RH 75.0%, closed) and acceleration.

About 1.4 g of sample was put into a double-layer LDPE bag, each layerof LDPE bag was fastened and sealed respectively, then the LDPE bag anda medicinal desiccant were put into an aluminum-foil bag and sealed byheating, under conditions of high temperature and high humidity, asample was taken on the 30^(th) day for detection, and a detectionresult was compared with an initial detection result on the 0^(th) day.The test result is shown in Table 3.

TABLE 3 Solid Stability Test of Amorphous Form of Compound Representedby Formula (II) Time Content Total Test condition point (%) impurity (%)—  0 day 99.3 1.56 High temperature and high 30 days 97.8 1.96 humidity(40° C./RH 75.0%, close)

The result showed that the amorphous form solid of the compound wasrelatively stable under the conditions of high temperature, highhumidity and sealing, and the total impurity did not increasesignificantly.

3. Solubility Experiment of Amorphous Form Sample of CompoundRepresented by Formula (II)

An equilibrium solubility of an amorphous form sample in pH 1.0/2.0(hydrochloric acid solution), pH 3.8/4.5/5.5 (acetate buffer solution),pH 6.0/6.8/7.4 (phosphate buffer solution) and water was detected(prepared according to the Technical Guiding Principles for DissolutionRate Test of Ordinary Oral Solid Preparations of Chinese Pharmacopoeia).

5 mL of different media (pH 1.0, pH 2.0, pH 3.8, pH 4.5, pH 5.5, pH 6.0,pH 6.8 and pH 7.4 buffer solutions and pure water) were respectivelyadded into nine 8 mL glass bottles, and an appropriate amount ofamorphous form sample was added respectively to make the mixture asuspension. Magnetic stirring bars were added into the sample above,which are placed on a magnetic stirrer to stir (at a temperature of 37°C.).

The sample was centrifuged after 24 h, and a supernatant was taken froman upper sample to determine a concentration thereof by HPLC and a pHvalue thereof (results shown in Table 4).

TABLE 4 Solubility Result of Amorphous Form Sample of CompoundRepresented by Formula (II) in Different pH Media 24 h SolubilityMenstruum pH State (mg/mL)  0.1 NHCl 1.02 Turbid 0.398 0.01 NHCl 2.01Turbid 1.629 pH 3.8 buffer solution 3.68 Turbid 15.097 pH 4.5 buffersolution 4.48 Turbid 19.637 pH 5.5 buffer solution 5.25 Turbid 18.723 pH6.0 buffer solution 5.89 Turbid 0.013 pH 6.8 buffer solution 6.75 Turbid0.003 pH 7.4 buffer solution 7.20 Turbid <LOQ Water 4.28 Turbid 13,541LOQ (quantitative LOQ = 0.0003 mg/mL, S/N = 22 detection limit)

The result showed that the amorphous form solid of the compound waseasily soluble in a hydrochloric acid solution, an acetate buffersolution and water, and was slightly soluble or insoluble in a phosphatebuffer solution.

4. Hygroscopicity Test of Amorphous Form Sample of Compound Representedby Formula (II)

A hygroscopicity of an amorphous form sample was detected. (Thehygroscopicity of the compound was determined according to the method inthe General Rules of the Chinese Pharmacopoeia (2015 Version) VolumeIV).

Three dry glass weighing bottles with stoppers were weighed, the resultsof which were recorded as m₁ 1, m₁ 2 and m₁ 3. An appropriate amount ofcrude drug sample was spread in the weighed weighing bottles (the samplehas a thickness of about 1 mm), then accurately weighed and recorded asm₂ 1, m₂ 2 and m₂ 3. The weighing bottles were open and placed togetherwith bottle caps in a dryer with saturated ammonium chloride solution ata lower part, the dryer was covered, then the dryer was placed in athermostat at 25° C. for 24 h. After being placed for 24 h, the weighingbottles were covered, then taken out for accurate weighing, the resultsof which were recorded as m₃ 1, m₃ 2 and m₃ 3. Weight increase byhygroscopicity was calculated, and the calculation formula was asfollows: weight increase percentage=100%×(m₃−m₂)/(m₂−m₁). (Ahygroscopicity result was shown in Table 5).

TABLE 5 Hygroscopicity Result of Amorphous Form Sample of CompoundRepresented by Formula (II) Weight Batch increase No. of percentageAverage sample m₁ (mg) m₂ (mg) m₃ (mg) (%) value (%) 1 34106.47 35042.3835086.50 4.714 5.24 2 33971.43 34826.02 34875.50 5.790 3 35198.4936030.94 36074.35 5.215

Experimental conclusion: according to the hygroscopicity test result, anaverage weight increase of hygroscopicity of the amorphous form samplewas 5.24%, which was less than 15% but not less than 2%, and thecompound had hygroscopicity.

Drug Metabolism Experiment

Experimental Purpose:

Through the experiment of drug metabolism in a mouse, the metabolism ofthe compound in the mouse is evaluated by taking C_(max), t_(1/2), AUC,MRT and B/P ratio in vivo as indexes.

1. Pharmacokinetic Study of Parent Compound a and Prodrug B Thereof (theSpecific Structures were Represented by Formulas A and B)Intramuscularly Injected in Mouse

A test compound was mixed with an appropriate amount of sesame oil, andthe mixture was vortexed and ultrasonically processed to obtain an evensuspension of 25 μmol/mL. A SD mouse aged 6 weeks to 9 weeks (ShanghaiSLAC Laboratory Animal Co., Ltd) was selected and intramuscularlyinjected with a suspension of the test compound at a dose of 20 μmol/kgor 40 μmol/kg. Whole blood of a certain period of time was collected,and a precipitant (acetonitrile, methanol and internal standard foranalysis) was added and centrifuged. A supernatant solution was analyzedfor a drug concentration by a LC-MS/MS method (if the test drug was theprodrug, concentrations of the prodrug and the hydrolyzed parent drugwere analyzed simultaneously), and pharmacokinetic parameters werecalculated by Phoenix WinNonlin software (Pharsight Company of theUnited States).

TABLE 6 Pharmacokinetic Experiment Result of Intramuscular Injection ofCarboxylate Diester Prodrug of Compound A Compound B Parent Compound No.Compound B compound A C_(max) (nM) ND 192 T_(max) (hr) ND 2.17 t_(1/2)(hr) ND 33.7 AUG)_(0-last) (nM · hr) ND 3235 MRT₀-last (hr) ND 18.0

Note: the dosage of all the compounds was 20 μmol/kg. Each 20 μmol ofthe carboxylate diester prodrug could theoretically hydrolyze to produce40 μmol of active components of a compound 21.

ND=not determined (parameters could not be determined because an endeliminated phase could not be fully defined)

Compound A was free alkali of the compound 1-16 before salt formation

Compound B is free alkali of the compound represented by formula (II)before salt formation

The pharmacokinetic experiment result of the intramuscular injectionproves that a sesame oil suspension of the carboxylate diester prodrugof the compound A is slowly released in vivo after intramuscularinjection and quickly hydrolyzed into the parent drug compound A, whichcan significantly prolong a retention time of the parent drug compound Ain the mouse and reduce C_(max), thus achieving the purpose ofprolonging a drug action time and improving the safety.

The invention claimed is:
 1. A crystal form of a compound represented byformula (I),

wherein an X-ray powder diffraction spectrum of the crystal formcomprises characteristic peaks at 2θ values of 13.07°±0.2°, 16.84±0.2°,18.51±0.2°, 24.04°±0.2°, and 26.20°±0.2°.
 2. The crystal form accordingto claim 1, wherein the X-ray powder diffraction spectrum of the crystalform comprises characteristic peaks at 2θ values of 13.07°±0.2°,15.30°±0.2°, 16.84°±0.2°, 18.51°±0.2°, 21.44°±0.2°, and 23.18°±0.2°. 3.The crystal form according to claim 2, wherein the X-ray powderdiffraction spectrum of the crystal form is shown in FIG.
 4. 4. Thecrystal form according to claim 1, wherein a DSC curve of the crystalform comprises two endothermic peaks at 73.71° C.±3° C. and 245.82°C.±3° C.
 5. The crystal form according to claim 4, wherein the DSC curveof the crystal form is shown in FIG.
 5. 6. The crystal form according toclaim 1, wherein at 120.00° C.±3° C. of a TGA curve of the crystal form,a weight is reduced by 5.812%; and at 200.12° C.±3° C. of the TGA curveof the crystal form, the weight is reduced by 6.5748%.
 7. The crystalform according to claim 6, wherein the TGA curve of the crystal form isshown in FIG. 6.